Gender and age normalization and ventilation efficiency during exercise in heart failure with reduced ejection fraction

on behalf of MECKI score research group, Elisabetta Salvioni, Ugo Corrà, Massimo Piepoli, Sara Rovai, Michele Correale, Stefania Paolillo, Mario Pasquali, Damiano Magrì, Giuseppe Vitale, Laura Fusini, Massimo Mapelli, Carlo Vignati, Rocco Lagioia, Rosa Raimondo, Gianfranco Sinagra, Federico Boggio, Lorenzo Cangiano, Giovanna Gallo, Alessandra MaginiMauro Contini, Pietro Palermo, Anna Apostolo, Beatrice Pezzuto, Alice Bonomi, Angela B. Scardovi, Pasquale Perrone Filardi, Giuseppe Limongelli, Marco Metra, Domenico Scrutinio, Michele Emdin, Lucrezia Piccioli, Carlo Lombardi, Gaia Cattadori, Gianfranco Parati, Sergio Caravita, Federica Re, Mariantonietta Cicoira, Maria Frigerio, Francesco Clemenza, Maurizio Bussotti, Elisa Battaia, Marco Guazzi, Francesco Bandera, Roberto Badagliacca, Andrea Di Lenarda, Giuseppe Pacileo, Claudio Passino, Susanna Sciomer, Giuseppe Ambrosio, Piergiuseppe Agostoni

Research output: Contribution to journalArticlepeer-review


Aims: Ventilation vs. carbon dioxide production (VE/VCO2) is among the strongest cardiopulmonary exercise testing prognostic parameters in heart failure (HF). It is usually reported as an absolute value. The current definition of normal VE/VCO2 slope values is inadequate, since it was built from small groups of subjects with a particularly limited number of women and elderly. We aimed to define VE/VCO2 slope prediction formulas in a sizable population and to test whether the prognostic power of VE/VCO2 slope in HF was different if expressed as a percentage of the predicted value or as an absolute value. Methods and results: We calculated the linear regressions between age and VE/VCO2 slope in 1136 healthy subjects (68% male, age 44.9 ± 14.5, range 13–83 years). We then applied age-adjusted and sex-adjusted formulas to predict VE/VCO2 slope to HF patients included in the metabolic exercise test data combined with cardiac and kidney indexes score database, which counts 6112 patients (82% male, age 61.4 ± 12.8, left ventricular ejection fraction 33.2 ± 10.5%, peakVO2 14.8 ± 4.9, mL/min/kg, VE/VCO2 slope 32.7 ± 7.7) from 24 HF centres. Finally, we evaluated whether the use of absolute values vs. percentages of predicted VE/VCO2 affected HF prognosis prediction (composite of cardiovascular mortality + urgent transplant or left ventricular assist device). We did so in the entire cardiac and kidney indexes score population and separately in HF patients with severe (peakVO2 <14 mL/min/kg, n = 2919, 61.1 events/1000 pts/year) or moderate (peakVO2 ≥ 14 mL/min/kg, n = 3183, 19.9 events/1000 pts/year) HF. In the healthy population, we obtained the following equations: female, VE/VCO2 = 0.052 × Age + 23.808 (r = 0.192); male, VE/VCO2 = 0.095 × Age + 20.227 (r = 0.371) (P = 0.007). We applied these formulas to calculate the percentages of predicted VE/VCO2 values. The 2-year survival prognostic power of VE/VCO2 slope was strong, and it was similar if expressed as absolute value or as a percentage of predicted value (AUCs 0.686 and 0.690, respectively). In contrast, in severe HF patients, AUCs significantly differed between absolute values (0.637) and percentages of predicted values (0.650, P = 0.0026). Moreover, VE/VCO2 slope expressed as a percentage of predicted value allowed to reclassify 6.6% of peakVO2 <14 mL/min/kg patients (net reclassification improvement = 0.066, P = 0.0015). Conclusions: The percentage of predicted VE/VCO2 slope value strengthens the prognostic power of VE/VCO2 in severe HF patients, and it should be preferred over the absolute value for HF prognostication. Furthermore, the widespread use of VE/VCO2 slope expressed as percentage of predicted value can improve our ability to identify HF patients at high risk, which is a goal of utmost clinical relevance.
Original languageEnglish
JournalESC heart failure
Publication statusAccepted/In press - Nov 11 2019


  • Cardiopulmonary exercise test
  • Heart failure
  • Prognosis
  • Ventilation efficiency


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